Alzheimer's disease (AD) is currently the most actively studied neurodegenerative disease. AD is clinically characterized by progressive amnesia and cognitive impairment, and pathlogically characterized by a wide range of neuronal loss, intraneuronal tangles, and extracellular senile plaques that have congophilic dense core. Effective treatment for AD still does not exist. It is generally accepted that not all, but many of the clinical manifestations of this disease are explained by progressive neuronal death. Elucidation of pathological mechanism of the onset of neuronal death in AD, to prevent AD is essential for developing novel effective treatments for AD.
Four different groups of mutant genes are known to cause early-onset familial AD (FAD): V642I/F/G APP (the number represents the position in APP695, an APP consisting of 695 amino acids); K595N/M696L (NL-APP); presenilin (PS)-1 mutants; and PS-2 mutants (Shastry, B. S. and Giblin, F. J. (1999) Brain Res. Bull. 48, 121-127). Yamatsuji et al. suggested that these FAD genes might cause cell death of neurons, based on the observation on nerve cell line F11 wherein three V642 type mutant cDNA of APP was transiently expressed (Yamatsuji, T. et al. (1996) Science 272, 1349-1352). The result was also confirmed by experiments that used primary cultured neurons and other nerve cell lines (Zhao, B. et al. (1997) J. Neurosci. Res. 47, 253-263; Luo, J. J. et al. (1999) J. Neurosci. Res. 55, 629-42). Further, Wolozin et al. revealed that FAD-linked mutant N1411 PS-2 significantly enhances cell mortality in PC12 cells, and that FAD-linked mutant PS-1 induces apoptosis of T lymphocytes (Wolozin, B. et al. (1996) Science 274, 1710-1713; Wolozin, B. et al. (1998) Neurobiol. Aging 19, S23-27). Furthermore, regarding PS-1, enhanced sensitivity to neuronal death induced by Aβ addition and/or trophic factor deficiency due to the expression of PS-1 mutant (Guo, Q. et al. (1996) Neuroreport 8, 379-83; Zhang, Z. et al. (1998) Nature 395, 698-702; Guo, Q. et al. (1999) Proc. Natl. Acad. Sci. U.S.A. 96., 4125-30); and enhanced sensitivity to neuronal death by trophic factor deficiency in cultured cortical neurons, derived from transgenic rats overexpressing wild-type PS-1, compared with those in non-transgenic controls (Czech, C. et al. (1998) Neuroscience 87, 325-36); and such have been repeatedly observed. Although it is controversial whether the mutant PS-1 is a stimulation factor of neuronal death or has no effect on neuronal death (Weihl, C. C. et al. (1999) J. Neurosci. 19, 5360-9; Bursztajn, S. et al. (1998) J. Neurosci. 18, 9790-9), it is highly possible that all of the four types of known FAD genes (V642-type mutant APP, NL-APP, PS-1 mutant, and PS-2 mutant) induce neuronal death or amplify the vulnerability of neurons to other cell death stimuli under certain conditions. Therefore, finding molecules that suppress AD gene-induced cell death observed in neurons in suggested to be the most important key for developing methods to treat AD.